Summary Drug safety issues pose a serious challenge to the health and well-being of patients. The development of our innovative technology aims to address a significant gap in the in vitro assessment of drug-induced cardiotoxicity, which is the number one reason for withdrawals of all marketed drugs as well as the premature termination of promising drug development candidates. Pressured by the enormous social and economic consequence, today?s drug safety professionals are facing daunting challenges to 1) improve accuracy in predicting the cardiac liability of candidate drugs; 2) increase assay throughput to afford earlier evaluation of larger number of compounds; and 3) reduce assay cost to mitigate the fast-rising spending on drug development. Recent advances in human stem cell-derived cardiomyocyte (hSC-CM) research demonstrate significant advantages over traditional in vitro model such as immortalized hERG cell lines. Compared to single-parameter hERG assay, hSC-CM provides an integrated action potential, a powerful biomarker for arrhythmia, from an intact human-based physiologic system. In addition the potential ability to generate unlimited, patient-specific, induced pluripotent stem cell (iPSC- CM) opens a tantalizing opportunity to model disease for individual patients, and for ?preclinical? human trials that would closely reflect the diversity of drug responses in the entire population. This has prompted an FDA initiative (Comprehensive In vitro Proarrhythmia Assessment or CiPA) that proposes the use of hSC-CMs for the electrophysiological assessment of proarrhythmia risk?a primary form of cardiotoxicity?for all drugs. Yet despite the pressing need to meet FDA?s impending regulatory requirements, drug safety professionals do not have an effective technology that affords high data quality (single cell resolution, physiological relevance, long-term measurement); high throughput; and low-cost analysis of transmembrane action potential from hSC-CM. Existing technologies, namely the patch clamp (for intracellular electrophysiology) and the planar multiple electrode array (MEA, for extracellular electrophysiology), addresses either data quality or throughput to an extent, but never both. The lack of adequate environmental control for both technologies further reduces the physiological relevance of the results. The novel electrophysiology platform proposed in this STTR application provides a powerful solution that bridges the longstanding gap between high-quality, low throughput intracellular electrophysiology and low-quality, high-throughput extracellular electrophysiology; and for the first time enables the measurement of hSC-CMs under optimal physiological conditions. Central to this system is the seamless integration of two innovative approaches: 1) parallel, nano- fabricated biocompatible electrodes and 2) sensitive, environmentally robust electronics. In combination, our breakthrough technology provides a significantly improved cellular electrophysiology platform, with an immediate and positive impact on the cardiotoxicity assessment using human stem cell-derived cardiomyocytes. This tool, with further development, can afford requirements for even higher throughput, and other electrophysiology applications such as network analysis using stem cell-derived neurons.